Transdermal (i.e., through the skin) delivery of therapeutic agents (e.g., drugs) is an important medicament administration route. Transdermal drug delivery bypasses gastrointestinal degradation and hepatic metabolism. Most commercial transdermal drug delivery systems (e.g., nitroglycerin, scopolamine, estradiol, testosterone skin patches) deliver drug by passive diffusion. The drug diffuses from a reservoir in the patch into the skin of the patient by means of the concentration gradient which exists, i.e., the drug diffuses from the high concentration in the patch reservoir to the low concentration in the patient's body. The flux of drug through a patient's skin is determined by a number of factors including the drug's partition coefficient and solubility characteristics. This type of delivery system (i.e., a patch) provides slow, but controlled, delivery of the drug to a patient's blood stream. Transdermal drug delivery is an especially attractive administration route for drugs with a narrow therapeutic index, short half-life and potent activity.
Unfortunately, many drugs exhibit transdermal diffusion fluxes which are too low to be therapeutically effective. This is especially true for high molecular weight drugs such as polypeptides and proteins. To enhance transdermal drug flux, a technique involving application of low levels of electric current applied through a drug reservoir in contact with a patient's body surface (e.g., skin) has been used. This technique has been called by several names including iontophoresis and, more recently, electrotransport.
Electrotransport is a process by which the transdermal transport of therapeutic agents or species is achieved by using an electrical current as the driving force, i.e., by the application of an electric current to the patient through an agent-containing reservoir. As such, electrotransport is a more controllable process than passive transdermal drug delivery since the amplitude, timing and polarity of the applied electric current is easily regulated using standard electrical components. In general, electrotransport drug flux can be from 50% to several orders of magnitude greater than passive transdermal flux of the same drug.
In presently known electrotransport devices, at least two electrodes are used. Both of these electrodes are positioned in intimate electrical contact with some portion of the patient's body surface (e.g., skin). One electrode, called the active or donor electrode, is the electrode from which the (e.g., ionic or ionizable) therapeutic agent, drug precursor or drug is delivered into the body by electrotransport. The other electrode, called the counter or return electrode, serves to close the electrical circuit through the body. In conjunction with the patient's body surface contacted by the electrodes, the circuit is completed by connection of the electrodes to a source of electrical energy, e.g., a battery.
Depending upon the electrical charge of the species to be delivered transdermally, either the anode or cathode may be the “active” or donor electrode. If, for example, the ionic substance to be delivered into the body is positively charged (i.e., a cation), then the anode will be the active electrode and the cathode will serve to complete the circuit. On the other hand, if the ionic substance to be delivered is relatively negatively charged (i.e., an anion), then the cathodic electrode will be the active electrode and the anodic electrode will be the counter electrode.
Alternatively, both the anode and the cathode may be used to deliver drugs of appropriate charge into the body. In such a case, both electrodes are considered to be active or donor electrodes. That is to say, the anodic electrode can deliver positively charged agents into the body while the cathodic electrode can deliver negatively charged agents into the body.
Existing electrotransport devices generally require a reservoir or source of the therapeutic agent that is to be delivered into the body by electrotransport; the agent is typically in the form of a liquid solution of an ionized or ionizable species, or a precursor of such species. Examples of such reservoirs or sources include a pouch as described in Jacobsen, U.S. Pat. No. 4,250,878; a pre-formed gel body as disclosed in Webster, U.S. Pat. No. 4,382,529; and a glass or plastic container holding a liquid solution of the drug as disclosed in the figures of Sanderson et al., U.S. Pat. No. 4,722,726. Such drug reservoirs are electrically connected to the anode or to the cathode of the electrotransport device to provide a fixed or renewable source of one or more desired species or agents.
The term “electrotransport” as used herein, refers generally to the electrically assisted delivery of a therapeutic agent, whether the agent to be delivered is completely charged (i.e., 100% ionized), completely uncharged, or partly charged and partly uncharged. The therapeutic agent or species may be delivered by electromigration, electroosmosis, electroporation or any combination thereof. Electroosmosis, in general, results from the migration of liquid solvent, in which the species is contained, as a result of the application of electromotive force to the therapeutic species reservoir. Electroporation involves the formation of transiently existing pores which occur upon applying electric current to the skin.
Of particular interest is the transdermal electrotransport delivery of peptides, polypeptides, and proteins because of the problems encountered with more common drug administration routes such as oral delivery. Polypeptide and protein molecules are highly susceptible to degradation by proteolytic enzymes in the gastrointestinal tract and are subjected to an extensive hepatic metabolism when taken orally. Polypeptides and proteins usually require parental administration to achieve therapeutic levels in the patient's blood. The most conventional parenteral administration techniques are hypodermic injections and intravenous administration. Polypeptides and proteins are, however, inherently short acting in their biological activity, requiring frequent injections, often several times a day, to maintain the therapeutically effective levels needed. Patients frequently find this treatment regimen to be inconvenient, painful and with an attendant risk of, e.g., infection.
Much effort has been expended to find other routes (other than parenteral injections) for effective administration of pharmaceutical polypeptides and proteins. Administration routes with fewer side effects as well as better patient compliance have been of particular interest. Such alternative routes have generally included “shielded” oral administration wherein the polypeptide/protein is released from a capsule or other container after passing through the low pH environment of the stomach, delivery through the mucosal tissues, e.g., the mucosal tissues of the lung with enhalers or the nasal mucosal tissues with nasal sprays, and implantable pumps. Unfortunately to date, these alternative routes of polypeptide/protein delivery have met with only limited success.
Electrotransport delivery of polypeptides and proteins has also encountered technical difficulties. For example, water is the preferred liquid solvent for forming the solution of the drug being delivered by electrotransport due to its excellent biocompatability. Unfortunately, many polypeptides and proteins are unstable (i.e., they become hydrolyzed, oxidized, denatured or otherwise degraded) in the presence of water. The skin also contains proteolytic enzymes which may degrade the polypeptide/protein as it is delivered transdermally. In addition, certain polypeptides/proteins, particularly those that are not native to the animal being treated, may cause skin reactions, e.g., sensitization or irritation.
A number of investigators have disclosed electrotransport delivery of polypeptides and proteins. An early study by R. Burnette et al., J. Pharm. Sci., vol. 75 (1986) 738, involved the in vitro skin permeation of thyrotropin releasing hormone, a small tripeptide molecule. The electrotransport flux was found to be higher than passive diffusional flux. Chien et al., J. Pharm. Sci., vol. 78 (1988) 376, in both in vitro and in vivo studies, showed that transdermal delivery of vasopressin and insulin via electrotransport was possible. See, also, Maulding et al., U.S. Statutory Invention Registration No. H1160, which discloses electrotransport delivery of calcitonin in minipigs.
A number of approaches (other than simply increasing the applied levels of electrotransport current) have been used to enhance transdermal electrotransport flux of polypeptide and protein drugs. One approach involves the use of flux enhancers such as ionic surfactants. See, e.g., Sanderson et al., U.S. Pat. No. 4,722,726. Another approach uses cosolvents other than just water to enhance electrotransport flux. See, e.g., European Patent Application 0278 473. Yet another approach involves mechanically disrupting the outer layer (i.e., the straum corneum) of the skin prior to electrotransport delivery therethrough. See, e.g., Lee et al., U.S. Pat. No. 5,250,023.
Further approaches to enhancing transdermal electrotransport drug flux involve creating a prodrug or an analog of the drug of interest and electrotransporting the prodrug or modified analog. For example, WO 92/12999 discloses delivery of insulin as an insulin analog having a reduced tendency to self-associate (apparently associated forms of insulin present in conventional pharmaceutical compositions reduce transdermal delivery of the insulin). The analogs are created by substituting aspartic acid (Asp) or glutamic acid (Glu) for other amino acid residues at selected positions along the insulin polypeptide chain. WO 93/25197 discloses delivery of both peptide and non-peptide drugs as pharmaceutical agent-modifier complexes or prodrugs wherein a chemical modifier (e.g., a charged moiety) is covalently bonded to the parent pharmaceutical agent. The covalent bond is broken after the agent is delivered into the body, thereby releasing the parent agent.
While the problems associated with electrotransport delivery of proteins and polypeptides have been recognized and attempts to improve the electrotransport flux of polypeptide and protein drugs have been advanced, there still exists a need to provide a method for achieving higher transdermal electrotransport flux of polypeptides and proteins.